Pulmonary hypertension (PH) covers a group of conditions characterized by an increase in pulmonary vascular resistance leading to right ventricular (RV) failure and premature death. Various pathological processes are involved in progression to heart failure (HF) secondary to PH, particularly myocardial injury, vascular remodeling and neurohormonal activation due to right chamber pressure overload. Risk stratification is crucial for prognostic and therapeutic assessment, as well as for the prescription and titration of new vasodilators. Stratification is usually based on exercise capacity, echocardiography, and hemodynamic assessment by cardiac catheterization.1 However, the value of many of these parameters is limited, as they are subjective in nature, operator-dependent and/or invasive.

In recent years the prognostic value of several biomarkers has been investigated in PH2 that may provide an efficient and noninvasive means for risk stratification and monitoring. In the international guidelines, only measurement of brain natriuretic peptide or its N-terminal portion (NT-proBNP) is recommended in everyday practice.1 Nevertheless, the value of NT-proBNP is limited for prognostic stratification, particularly in the presence of concomitant left heart disease or renal failure. Furthermore, various studies have suggested that significant elevation of serum NT-proBNP only occurs late, at a stage when there is marked ventricular dilatation and adjustment of therapy may no longer be effective.3

Given the complexity of the mechanisms underlying PH, the value of a multi-biomarker approach is being investigated. Clinical research has mainly focused on prognostic stratification of patients with left HF, and the most promising biomarkers have only been tested in small groups of PH patients with right HF, which limits the validity of the results. Several biomarkers studied in left HF reflect biological processes that may be of more relevance in progression of PH, particularly those related to pulmonary vascular remodeling (endothelial dysfunction, thrombosis in situ and oxidative stress) and RV overload. There is thus a pressing need to investigate biomarkers such as soluble ST2 (sST2, the interleukin-33 receptor), plasma renin, adrenomedullin and endothelin-1 (ET-1).

sST2 is a biomarker with multiple effects in vivo. Its expression is upregulated in cardiac fibroblasts and cardiomyocytes exposed to mechanical strain.4 Studies have documented increased serum sST2 levels in acute HF and suggest a correlation with remodeling and fibrosis in chronic HF.5 However, its prognostic value in right HF secondary to PH is unknown.

Various studies have demonstrated that chronic upregulation of the renin-angiotensin-aldosterone system (RAAS) in patients with left HF has significant prognostic implications, but its relevance in right HF secondary to PH is uncertain and the predictive value of plasma renin has never been established in this patient group.

Adrenomedullin, a vasoactive peptide with natriuretic properties produced in various tissues, has been consistently associated with prognosis in left HF,6 but its role in prognostic stratification of PH patients has yet to be determined.

ET-1 is a potent vasoconstrictor and a therapeutic target in PH.7 Serum ET-1 levels are increased in various stages of HF, but studies with longer follow-up are needed to assess its prognostic impact.

The aim of the present study was to determine the prognostic value of new biomarkers and to assess the benefit of combining them in a multi-biomarker approach to predict outcome in right HF secondary to PH.

In this prospective study, we assessed the prognostic accuracy of new biomarkers (MR-proANP, renin, copeptin, ET-1, MR-proADM and sST2) in patients with right HF secondary to PH and compared it to that of conventional echocardiographic parameters. We confirmed the prognostic value of NT-proBNP and demonstrated for the first time that assessment of serum NT-proBNP, MR-proANP, renin and sST2 levels combined in a multi-biomarker score has additional value. The score showed a high degree of accuracy for prognostic stratification, identifying high-risk patients, who may thus benefit from early intensive multidisciplinary therapeutic interventions in the future.

The results of the study indicate that the new biomarkers are valuable prognostic markers and that their clinical application would bring benefits. It is also important to remember that these results were obtained in a population of patients with right HF secondary to PH (confirmed by right heart catheterization) that was relatively heterogeneous in terms of etiology, but the prognostic accuracy of the biomarkers studied did not differ significantly according to the Nice classification. This is of relevance for everyday clinical practice, since prognostic stratification using these biomarkers can be applied to all the various clinical forms of PH.

The study also confirmed that there is a relationship between RA and RV anatomical and functional parameters and prognosis. RV basal diameter and RA fractional area were strong independent predictors of prognosis, whereas RV functional parameters, while also correlating with prognosis, had less impact and were not independent predictors. This highlights the difficulty of echocardiographic assessment of global RV function, which is strongly affected by the altered ventricular-arterial coupling found in PH and possibly dependent on remodeling such as in wall hypertrophy.

Natriuretic peptides, considered the gold standard biomarkers in HF, play an important role in cardiovascular homeostasis, including regulation of vascular tone, blood volume and endothelial permeability, as well as in cardiac hypertrophy. Of these peptides, ANP and BNP, which are mainly produced in the atria and ventricles, respectively, are of particular importance.15 Both are secreted in response to myocardial stretching secondary to pressure or volume overload. The biological functions of ANP and BNP include various compensatory mechanisms, such as natriuresis, diuresis and vasodilation.16

Most studies on B-type peptides have focused on BNP or NT-proBNP. The prognostic value of these peptides has been well documented in all stages of left HR, and is additional to other clinical markers. For example, the ADHERE registry17 found a linear relationship between BNP levels and mortality in patients hospitalized for decompensated HF, even after adjustment for other laboratory or clinical risk markers.

Besides its natriuretic effects, ANP has potent pulmonary vasodilatory properties.18 It has a very short plasma half-life (2-5 min),19 which makes it difficult to measure. Research has thus focused on assessment of MR-proANP, a more biologically stable peptide, whose prognostic value has been assessed in patients with left HF. In the PRIDE study,20 MR-proANP was identified as an independent predictor of mortality in patients with decompensated HF, and the BACH trial21 demonstrated the non-inferiority of MR-proANP compared to BNP in diagnosing acute HF in patients with acute dyspnea; furthermore, data from this trial suggested that MR-proANP had greater accuracy in gray areas of BNP and in obese patients.

The prognostic value of natriuretic peptides has been investigated in the context of PH and RV failure, but the results are limited. Some studies have demonstrated that plasma BNP and NT-proBNP levels increase in proportion to the degree of RV dysfunction22 and reduction in functional capacity,23 but the prognostic value of MR-proANP has not been assessed. The results of our study are therefore of particular interest, suggesting there are advantages to combined assessment of these peptides for risk stratification. NT-proBNP was associated predominantly with mortality (and short-term risk), while MR-proANP was an independent predictor of death or hospitalization (longer-term risk of events). Patients with the highest levels of NT-proBNP (third tertile: >1398 pg/ml) had a six-fold greater risk of death and those in the third tertile for MR-proANP had a three-fold greater risk of death or hospitalization for worsening PH. We also showed that combining these biomarkers increased the accuracy of prognostic stratification. This supports the hypothesis that natriuretic peptides are an integral part of the physiological counter-regulatory response in patients with PH and RV dysfunction, and hence have predictive value.

These results could be of even more interest as these peptides may soon become a therapeutic target. For example, it has been demonstrated that administration of ANP significantly decreased vasoconstriction and adverse remodeling in an animal model of PH.24

Natriuretic peptides have inhibitory effects on the RAAS.25 The prognostic importance of increased RAAS activity is widely accepted in left HF,25 but its impact in right HF is still uncertain. Studies suggest that the RAAS is upregulated in PH as a compensatory mechanism, although this may have long-term negative effects.26 However, little is known about alterations in RAAS signaling in PH. Two separate studies have reported that certain angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor polymorphisms are associated with more rapid progression of idiopathic PH, suggesting involvement of the RAAS.27,28 Elevated aldosterone levels were recently described as triggering pulmonary vascular disease in experimental models of PH,29 and Maron et al.30 reported that plasma aldosterone levels correlated positively with hemodynamic parameters (pulmonary vascular resistance and transpulmonary gradient) in patients with PH.

Forfia et al.31 demonstrated an association between hyponatremia (an indirect indicator of RAAS activity), right HF and poor survival in patients with PH, but our results did not reveal a significant association between natremia and risk of events after adjustment for other variables. This probably reflects the complexity of the underlying mechanisms and changes in the predictive value of sodium levels due to anticongestive therapy. Our study assessed parameters that are a more direct measure of RAAS activity (ACE, renin and aldosterone), which have not been investigated systematically in long-term follow-up studies. We found that patients who had an unfavorable clinical course presented elevated baseline renin, with no changes in ACE or aldosterone. These results highlight the complexity of the mechanisms involved, not only in terms of modulation of the RAAS itself but also the lack of an association between the extent of RAAS upregulation and disease severity. Possible explanations include the presence of other states of hyperaldosteronism (for example systemic hypertension), inter-individual differences in sodium homeostasis, and circadian factors that regulate aldosterone synthesis.32 Our results point to a potential role for therapies that act on the RAAS.

ET-1 and vasopressin are peptides with vasoconstrictive properties that play a fundamental role in cardiovascular physiology. Besides being a potent vasoconstrictor, ET-1 also has proliferative effects on vascular smooth muscle, and is involved in the pathophysiology of PH. Plasma ET-1 levels are significantly elevated in PH33 and correlate with disease severity,34 but their prognostic value has been little explored. Vasopressin, a peptide hormone secreted by the hypothalamus and stored in the neurohypophysis, has antidiuretic and vasoconstrictive properties. Its levels are elevated in HF,35 but it is difficult to measure due to its short half-life and the fact that it binds to plasma proteins. However, its C-terminal portion (copeptin) is stable and easily measured, and has been studied in the context of HF and acute coronary syndromes. In the BACH study,36 elevated copeptin was associated with higher 90-day mortality and hospitalization for cardiac causes. The prognostic value of copeptin has been demonstrated in both acute and chronic HF.37,38 Compared to left HF, the neurohormonal axis has been little studied in patients with PH and right HF. In our population, we found higher copeptin and ET-1 levels in individuals who had an unfavorable clinical course (death and/or hospitalization of cardiac causes).

ST2 is a member of the Toll-like/IL-1 receptor superfamily, with a soluble (sST2) and a transmembrane (ST2L) isoform; the ligand for both forms is interleukin-33 (IL-33). sST2 is a biomarker with pluripotent effects in vivo, whose expression is upregulated in cardiac fibroblasts and cardiomyocytes exposed to mechanical strain, and plays a role in remodeling and fibrosis in HF. Recent studies have demonstrated higher serum sST2 concentrations in acute HF, correlating significantly with adverse ventricular remodeling and prognosis.4,39 Sanada et al.40 showed that IL-33 acting through ST2L antagonizes myocyte hypertrophy induced by neurohormonal mechanisms. These authors also demonstrated that sST2 inhibits the cardioprotective effect of IL-33. Shimpo et al.41 reported that elevated serum sST2 levels were predictors of HF and mortality in patients with acute myocardial infarction. sST2 has been thoroughly studied in patients with dyspnea and suspected decompensated HF. In a subanalysis of the PRIDE study, Januzzi et al.42 assessed sST2 and NT-proBNP levels in patients with acute dyspnea and demonstrated that sST2 concentrations were higher in those with acute HF and that it had greater prognostic value than NT-proBNP. sST2 has also been shown to be a predictor of sudden cardiac death in patients with chronic HF.43

To summarize, sST2 is now considered a biomarker of severity and prognosis in HF, but few studies have assessed its role in right HF secondary to PH. Zheng et al.44 recently demonstrated a correlation between plasma sST2 levels and hemodynamic parameters in patients with idiopathic PH, while Carlomagno et al.45 reported a correlation between serum sST2 and RV dimensions and function assessed by cardiac magnetic resonance imaging. From a hemodynamic standpoint, patients with RV dysfunction present increased filling pressures, greater myocardial wall stress with ventricular stretching and high sST2 levels. This study consistently demonstrated the value of sST2 as a new prognostic marker in right HF, and given the importance of RV function in risk stratification of patients with PH,46 sST2 can be combined with other biomarkers, as in the risk stratification model proposed in this work.

The adaptation of the right heart to pressure overload and morphological changes arising from PH have been characterized by various imaging modalities, particularly echocardiography. Several studies have identified RA and RV morphological and functional prognostic predictors in these patients.47 Nevertheless, the relationship between anatomical deformation or chamber dilatation and parameters of RV dysfunction has yet to be fully clarified. Furthermore, parameters related to RV dilatation, rather than those related to RV function, appear to be more consistent for determining prognosis in these patients, particularly chamber dimensions and volumes, as assessed by echocardiography and magnetic resonance imaging, respectively.48 Studies of specific therapy in PH patients have found a correlation between these parameters and functional improvement.

The present study should be seen as an exploratory assessment of a relatively small population of patients with right HF secondary to PH confirmed by right heart catheterization, with limited follow-up. Moreover, the study population was heterogeneous in terms of PH etiology, disease duration and therapy at the time of recruitment and during follow-up. Its findings will have to be validated in larger prospective studies before they can be used in clinical decision-making. In addition, the impact of disease duration and therapy on the performance of the different prognostic predictors, both biomarkers and RA and RV anatomical and functional parameters, needs to be assessed.

This prospective study demonstrated that several new biomarkers (MR-proANP, renin, copeptin, ET-1, MR-proADM and sST2), together with NT-proBNP levels and parameters of right chamber dimensions and function, are valuable prognostic predictors in patients with right HF secondary to PH. It also showed for the first time that assessment of serum NT-proBNP, MR-proANP, renin and sST2 levels combined in a multi-biomarker score improves the accuracy of prognostic stratification. The score identified high-risk patients, who may thus benefit from early intensive multidisciplinary therapeutic interventions in the future.

The authors have no conflicts of interest to declare.